With the advancement of epigenetic science, there has been significant improvement in the field of cancer research. The epigenetic regulation in oral cancer however remains largely unresolved. This past year, 31,000 individuals were diagnosed with oral cancer in the US alone of which more than 50% of oral cancer patients were in the advanced stages at the time the cancer was detected. 1 out of 4 patients with oral cancer die due to delayed diagnosis. More detailed molecular mechanisms in the pathogenesis of oral cancer should be elucidated to ensure early detection and correct prognosis in oral cancer and to reduce morbidity and mortality. The long-term objective of this proposal is to understand the role of abrogated epigenetic regulation in oral carcinogenesis. Immediate objectives are to identify Cyclin Dependent Kinase 2-associating protein 1 (CDK2AP1), which is downregulated in 70% of oral cancer) mediated global and local methylation changes and to understand the molecular mechanism of CDK2AP1-mediated DNA methylation. This will be done by using methylation assays to profile global methylation and to identify differentially methylated target genes. Mechanism of CDK2AP1 function will be studied by disrupting the E2F/Rb pathway leading to changes in expression of DNA MethylTransferase 1 (DNMT1). To achieve these goals, two specific aims are proposed as follows: Specific Aim 1: Significance of CDK2AP1-mediated DNA methylation in oral keratinocytes. Specific Aim 2;Mechanism of CDK2AP1-mediated DNA methylation. The results of the proposed experiments will potentially be used to develop diagnostic tools to detect oral cancer at the onset of the disease development. The current scientific knowledge is not sufficient to make an early diagnosis for oral cancer patients. The proposed application and future vision will enhance current knowledge to bridge the gap between the present assessment of oral cancer and prognosis of the patient by studying the fundamental biology underlying the disease.